UBE3A, an E3 ligase in the ubiquitin-proteasomal system, plays important roles in brain development and brain function. Optimal CNS UBE3A expression is crucial since its deficiency results in Angelman syndrome, while its over-expression increases the risk for autism. In animal models, Ube3a deficiency also results in impaired long-term potentiation (LTP) induced by theta burst stimulation and enhanced long-term depression (LTD) induced by low frequency stimulation (NMDAR-dependent) or agonists of group I mGluRs in field CA1 of hippocampus. During the previous funding period, we showed that Ube3a ubiquitinates SK2, a Ca2+-activated small conductance potassium channel, and facilitates its removal from excitatory synapses. Ube3a deficiency results in enhanced postsynaptic SK2 levels and effectively inhibiting NMDAR activation, leading to LTP and LTD impairment. SK2 levels in cell membranes are also regulated by protein kinase A (PKA); PKA phosphorylates SK2 in the C-terminal domain and facilitates SK2 endocytosis. Whether there is interaction between PKA- and Ube3a-mediated regulations of SK2 synaptic localization remains unknown. In this proposal, we will use multidisciplinary approaches to test the hypothesis that Ube3a-mediated SK2 ubiquitination not only results in its endocytosis into early endosomes, but also inhibits SK2 recycling back to synaptic membranes, and that PKA and Ube3a jointly regulate synaptic SK2 levels. Although both PKA and Ube3a have been implicated in learning and memory and in synaptic plasticity, there is sparse knowledge regarding their potential cross talks. Likewise, while much has been learned on the regulation of synaptic targeting and recycling of AMPARs and NMDARs, little is known regarding the regulation of SK2 synaptic localization and trafficking, although SK2 channels play important roles in numerous neurobiological functions. Therefore, understanding the regulation of SK2 by Ube3a and PKA would shed light on basic neurobiological mechanisms, as well as on several neurological diseases.